Department of Experimental Hematology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.
Department of Biochemistry and Molecular Biomedicine, Faculty of Biology, University of Barcelona, Avda. Diagonal 643, Barcelona, 08028, Spain.
Nat Commun. 2022 Apr 19;13(1):2013. doi: 10.1038/s41467-022-29639-0.
Metabolic programs can differ substantially across genetically distinct subtypes of acute myeloid leukemia (AML). These programs are not static entities but can change swiftly as a consequence of extracellular changes or in response to pathway-inhibiting drugs. Here, we uncover that AML patients with FLT3 internal tandem duplications (FLT3-ITD) are characterized by a high expression of succinate-CoA ligases and high activity of mitochondrial electron transport chain (ETC) complex II, thereby driving high mitochondrial respiration activity linked to the Krebs cycle. While inhibition of ETC complex II enhances apoptosis in FLT3-ITD AML, cells also quickly adapt by importing lactate from the extracellular microenvironment. C-labelled lactate metabolic flux analyses reveal that AML cells use lactate as a fuel for mitochondrial respiration. Inhibition of lactate transport by blocking Monocarboxylic Acid Transporter 1 (MCT1) strongly enhances sensitivity to ETC complex II inhibition in vitro as well as in vivo. Our study highlights a metabolic adaptability of cancer cells that can be exploited therapeutically.
代谢程序在不同遗传亚型的急性髓系白血病（AML）之间可能有很大差异。这些程序不是静态实体，而是可以随着细胞外变化或对途径抑制药物的反应而迅速改变。在这里，我们发现具有 FLT3 内部串联重复（FLT3-ITD）的 AML 患者表现出琥珀酸-CoA 连接酶的高表达和线粒体电子传递链（ETC）复合物 II 的高活性，从而驱动与三羧酸循环相关的高线粒体呼吸活性。虽然抑制 ETC 复合物 II 会增强 FLT3-ITD AML 中的细胞凋亡，但细胞也会迅速适应，从细胞外微环境中摄取乳酸。C 标记的乳酸代谢通量分析显示，AML 细胞将乳酸用作线粒体呼吸的燃料。通过阻断单羧酸转运蛋白 1（MCT1）抑制乳酸转运强烈增强了体外和体内对 ETC 复合物 II 抑制的敏感性。我们的研究强调了癌细胞的代谢适应性，这可以在治疗上得到利用。
